A Structure-function Analysis of the Nef Protein of Primate Lentiviruses

Nef is one of the five so-called auxiliary genes of primate lentiviruses, a group that also includes vif, vpr, vpu (in HIV-1 and SIVCPZ), and vpx (in HIV-2 and other SIV strains). Inactivating these genes does not completely prevent viral replication in cell culture (reviewed in (Cullen, 1998)), but studies conducted both in SIV-infected monkeys and in HIV-infected individuals have revealed that they encode important virulence factors. Three major functions of Nef have been uncovered through in vitro analyses: the downregulation of CD4 and MHC class I, the stimulation of virion infectivity, and the capacity to alter the activation state of cells.

[1]  D. Trono,et al.  The Nef protein of HIV-1 associates with rafts and primes T cells for activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[2]  C. Aiken,et al.  Association of Nef with the Human Immunodeficiency Virus Type 1 Core , 1999, Journal of Virology.

[3]  W. Greene,et al.  Cutting edge: SIV Nef protein utilizes both leucine- and tyrosine-based protein sorting pathways for down-regulation of CD4. , 1999, Journal of immunology.

[4]  V. Sasseville,et al.  HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages , 1999, Nature Medicine.

[5]  J. Marsh,et al.  HIV-1 Nef increases T cell activation in a stimulus-dependent manner. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Cullen,et al.  Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by expression of the viral Nef protein , 1999, Current Biology.

[7]  D. Trono,et al.  Cell-surface expression of CD4 reduces HIV-1 infectivity by blocking Env incorporation in a Nef- and Vpu-inhibitable manner , 1999, Current Biology.

[8]  J. Mills,et al.  Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. , 1999, The New England journal of medicine.

[9]  M Geyer,et al.  Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. , 1999, Molecular cell.

[10]  D. Baltimore,et al.  The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. , 1999, Immunity.

[11]  M. Greenberg,et al.  Two elements target SIV Nef to the AP‐2 clathrin adaptor complex, but only one is required for the induction of CD4 endocytosis , 1999, The EMBO journal.

[12]  A. McMichael,et al.  Induction of Fas Ligand Expression by HIV Involves the Interaction of Nef with the T Cell Receptor ζ Chain , 1999, The Journal of experimental medicine.

[13]  S. Rhee,et al.  HIV-1 Nef plays an essential role in two independent processes in CD4 down-regulation: dissociation of the CD4-p56(lck) complex and targeting of CD4 to lysosomes. , 1999, Virology.

[14]  Jean Gruenberg,et al.  Nef-Induced CD4 Degradation A Diacidic-Based Motif in Nef Functions as a Lysosomal Targeting Signal through the Binding of β-COP in Endosomes , 1999, Cell.

[15]  Dana Gabuzda,et al.  Regulation of Human Immunodeficiency Virus Type 1 Infectivity by the ERK Mitogen-Activated Protein Kinase Signaling Pathway , 1999, Journal of Virology.

[16]  Yen-Liang Chen,et al.  Nef-Induced CD4 and Major Histocompatibility Complex Class I (MHC-I) Down-Regulation Are Governed by Distinct Determinants: N-Terminal Alpha Helix and Proline Repeat of Nef Selectively Regulate MHC-I Trafficking , 1999, Journal of Virology.

[17]  M. Greenberg,et al.  A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4 , 1998, Current Biology.

[18]  W. Greene,et al.  A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor , 1998, Current Biology.

[19]  A. Guimond,et al.  Nef Harbors a Major Determinant of Pathogenicity for an AIDS-like Disease Induced by HIV-1 in Transgenic Mice , 1998, Cell.

[20]  M. Pandori,et al.  Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Luciw,et al.  Role of the SH3-Ligand Domain of Simian Immunodeficiency Virus Nef in Interaction with Nef-Associated Kinase and Simian AIDS in Rhesus Macaques , 1998, Journal of Virology.

[22]  J. Lautenberger,et al.  Binding of c-Raf1 Kinase to a Conserved Acidic Sequence within the Carboxyl-terminal Region of the HIV-1 Nef Protein* , 1998, The Journal of Biological Chemistry.

[23]  A. McMichael,et al.  T Cell Responses and Viral Escape , 1998, Cell.

[24]  B. Cullen.  HIV-1 Auxiliary Proteins: Making Connections in a Dying Cell , 1998, Cell.

[25]  M. Greenberg,et al.  The SH3 domain‐binding surface and an acidic motif in HIV‐1 Nef regulate trafficking of class I MHC complexes , 1998, The EMBO journal.

[26]  M. Foti,et al.  Mechanism of Nef‐induced CD4 endocytosis: Nef connects CD4 with the μ chain of adaptor complexes , 1998, The EMBO journal.

[27]  H. Enslen,et al.  Modulation of HIV‐1 infectivity by MAPK, a virion–associated kinase , 1998, The EMBO journal.

[28]  A. di Caro,et al.  Grossly Defective nef Gene Sequences in a Human Immunodeficiency Virus Type 1-Seropositive Long-Term Nonprogressor , 1998, Journal of Virology.

[29]  F. Brodsky,et al.  Interactions between HIV1 Nef and vacuolar ATPase facilitate the internalization of CD4. , 1998, Immunity.

[30]  S. Le Gall,et al.  Nef interacts with the mu subunit of clathrin adaptor complexes and reveals a cryptic sorting signal in MHC I molecules. , 1998, Immunity.

[31]  Yen-Liang Chen,et al.  The Proteolytic Cleavage of Human Immunodeficiency Virus Type 1 Nef Does Not Correlate with Its Ability To Stimulate Virion Infectivity , 1998, Journal of Virology.

[32]  B. Walker,et al.  HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes , 1998, Nature.

[33]  I. Mellman,et al.  Inhibition of Endosome Function in CHO Cells Bearing a Temperature-sensitive Defect in the Coatomer (COPI) Component ε-COP , 1997, The Journal of cell biology.

[34]  F. Gu,et al.  Functional Dissection of COP-I Subunits in the Biogenesis of Multivesicular Endosomes , 1997, The Journal of cell biology.

[35]  B. Cullen,et al.  Human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus Nef use distinct but overlapping target sites for downregulation of cell surface CD4 , 1997, Journal of virology.

[36]  S. Arold,et al.  The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling. , 1997, Structure.

[37]  Frank Kirchhoff,et al.  Association of simian immunodeficiency virus Nef with cellular serine/threonine kinases is dispensable for the development of AIDS in rhesus macaques , 1997, Nature Medicine.

[38]  C. Aiken.  Pseudotyping human immunodeficiency virus type 1 (HIV-1) by the glycoprotein of vesicular stomatitis virus targets HIV-1 entry to an endocytic pathway and suppresses both the requirement for Nef and the sensitivity to cyclosporin A , 1997, Journal of virology.

[39]  A. McMichael,et al.  Evasion of Cytotoxic T Lymphocyte (CTL) Responses by Nef-dependent Induction of Fas Ligand (CD95L) Expression on Simian Immunodeficiency Virus–infected Cells , 1997, The Journal of experimental medicine.

[40]  S. Grzesiek,et al.  Refined solution structure and backbone dynamics of HIV‐1 Nef , 1997, Protein science : a publication of the Protein Society.

[41]  A. Abo,et al.  The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix , 1997, Journal of virology.

[42]  R. Norton,et al.  Solution structure of a polypeptide from the N terminus of the HIV protein Nef. , 1997, Biochemistry.

[43]  C. Cheng‐Mayer,et al.  The N-terminus of Nef from HIV-1/SIV associates with a protein complex containing Lck and a serine kinase. , 1997, Immunity.

[44]  C. Cheng‐Mayer,et al.  Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques , 1996, Current Biology.

[45]  T. Greenough,et al.  High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection , 1996, Journal of virology.

[46]  S. Grzesiek,et al.  The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR. , 1996, Biochemistry.

[47]  Bradley L. Smith,et al.  The HIV Nef Protein Associates with Protein Kinase C Theta* , 1996, The Journal of Biological Chemistry.

[48]  D. Richman,et al.  Producer-cell modification of human immunodeficiency virus type 1: Nef is a virion protein , 1996, Journal of Virology.

[49]  B. Chait,et al.  Crystal Structure of the Conserved Core of HIV-1 Nef Complexed with a Src Family SH3 Domain , 1996, Cell.

[50]  M. Krieger,et al.  A Single Point Mutation in -COP Results in Temperature-sensitive, Lethal Defects in Membrane Transport in a Chinese Hamster Ovary Cell Mutant (*) , 1996, The Journal of Biological Chemistry.

[51]  H. Kalbitzer,et al.  Human immunodeficiency virus type 1 Nef protein is incorporated into virus particles and specifically cleaved by the viral proteinase. , 1996, Virology.

[52]  S. Grzesiek,et al.  The solution structure of HIV-1 Nef reveals an unexpected fold and permits delineation of the binding surface for the SH3 domain of Hck tyrosine protein kinase , 1996, Nature Structural Biology.

[53]  F. Lemonnier,et al.  Endocytosis of major histocompatibility complex class I molecules is induced by the HIV–1 Nef protein , 1996, Nature Medicine.

[54]  G. Milanesi,et al.  Nef-CD4 physical interaction sensed with the yeast two-hybrid system. , 1996, Virology.

[55]  I. Mellman,et al.  Cytoplasmic coat proteins involved in endosome function , 1995, Cell.

[56]  J. S. Sullivan,et al.  Genomic Structure of an Attenuated Quasi Species of HIV-1 from a Blood Transfusion Donor and Recipients , 1995, Science.

[57]  R. Desrosiers,et al.  Identification of a nef allele that causes lymphocyte activation and acute disease in Macaque monkeys , 1995, Cell.

[58]  D. Trono,et al.  Nef stimulates human immunodeficiency virus type 1 proviral DNA synthesis , 1995, Journal of virology.

[59]  N. Sarver,et al.  HIV Accessory Proteins: Emerging Therapeutic Targets , 1995, Molecular medicine.

[60]  O. Danos,et al.  Human immunodeficiency virus type 1 Nef increases the efficiency of reverse transcription in the infected cell , 1995, Journal of virology.

[61]  A. Greenway,et al.  Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines , 1995, Journal of virology.

[62]  D. Baltimore,et al.  Proline‐rich (PxxP) motifs in HIV‐1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down‐regulation of CD4. , 1995, The EMBO journal.

[63]  S. Benichou,et al.  Physical interaction of the HIV-1 Nef protein with beta-COP, a component of non-clathrin-coated vesicles essential for membrane traffic. , 1994, The Journal of biological chemistry.

[64]  M. Harris,et al.  Myristoylation-dependent binding of HIV-1 Nef to CD4. , 1994, Journal of molecular biology.

[65]  C. Cheng‐Mayer,et al.  HIV-1 Nef leads to inhibition or activation of T cells depending on its intracellular localization. , 1994, Immunity.

[66]  S. Rhee,et al.  Human immunodeficiency virus type 1 Nef-induced down-modulation of CD4 is due to rapid internalization and degradation of surface CD4 , 1994, Journal of virology.

[67]  H. Kalbitzer,et al.  A possible regulation of negative factor (Nef) activity of human immunodeficiency virus type 1 by the viral protease. , 1994, European journal of biochemistry.

[68]  M. Lenburg,et al.  Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain , 1994, Cell.

[69]  M. Warmerdam,et al.  The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages , 1994, The Journal of experimental medicine.

[70]  D. Richman,et al.  The importance of nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes , 1994, The Journal of experimental medicine.

[71]  L. Ratner,et al.  Myristoylation-enhanced binding of the HIV-1 Nef protein to T cell skeletal matrix. , 1993, Virology.

[72]  J. Skowroński,et al.  CD4 down-regulation by nef alleles isolated from human immunodeficiency virus type 1-infected individuals. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[73]  J. Rothman,et al.  Budding from Golgi membranes requires the coatomer complex of non-clathrin coat proteins , 1993, Nature.

[74]  D. Baltimore,et al.  Kinetics of expression of multiply spliced RNA in early human immunodeficiency virus type 1 infection of lymphocytes and monocytes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[75]  R. Desrosiers,et al.  Importance of the nef gene for maintenance of high virus loads and for development of AIDS , 1991, Cell.

[76]  J. Garcia,et al.  Serine phosphorylation-independent downregulation of cell-surface CD4 by nef , 1991, Nature.

[77]  P. Argos,et al.  β-COP, a 110 kd protein associated with non-clathrin-coated vesicles and the golgi complex, shows homology to β-adaptin , 1991, Cell.

[78]  B. Guy,et al.  HIV F/3' orf encodes a phosphorylated GTP-binding protein resembling an oncogene product , 1987, Nature.

[79]  W. Heneine,et al.  Evidence of Nef truncation in human immunodeficiency virus type 2 infection. , 1998, The Journal of infectious diseases.

[80]  M. Foti,et al.  The HIV-1 Nef protein acts as a connector with sorting pathways in the Golgi and at the plasma membrane. , 1997, Immunity.

[81]  J L Sullivan,et al.  Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. , 1995, The New England journal of medicine.